title: Erythroid cells generated in the absence of specific β1-integrin heterodimers accumulate reactive oxygen species at homeostasis and are unable to mount effective antioxidant defenses.
abstract: We have previously reported that β1(Δ/Δ) mice have a markedly impaired response to hemolytic stress, but the mechanisms of this were unclear. In the present study we explored in detail quantitative, phenotypic and functional aspects of erythropoiesis at homeostasis in a large number of animals for each of 3 murine models with specific β1 heterodimer integrin deficiencies. We found that, at homeostasis, β1-deficient mice have a modest uncompensated anemia with ineffective erythropoiesis and decreased red blood cell survival. Mice lacking only α4 integrins (α4β1/α4β7) do not share this phenotype. There is an increased tendency for reactive oxygen species accumulation in β1(Δ/Δ) erythroid cells with decreased anti-oxidant defenses at homeostasis which are exaggerated after stress. Furthermore, expansion of erythroid cells in spleen post-stress is dependent on α5β1, likely through mechanisms activating focal adhesion kinase complexes that are distinct from α4β1-mediated responses. In vivo inhibition of focal adhesion kinase activation partially recapitulates the β1(Δ/Δ) stress response. Mice lacking all α4 and β1 integrins (double knockouts) had, at homeostasis, the most severe phenotype with selective impairment of erythroid responses. The fact that integrins participate in mitigating stress in erythroid cells through redox activation of distinct signaling pathways by specific integrin heterodimers is a link that has not been appreciated until now.
authors.affiliation: thalp@u.washington.edu.
authors.forename: Tatyana
authors.initials: T
authors.lastname: Ulyanova
authors.forename: Yi
authors.initials: Y
authors.lastname: Jiang
authors.forename: Steven M
authors.initials: SM
authors.lastname: Padilla
authors.forename: Thalia
authors.initials: T
authors.lastname: Papayannopoulou
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000378:metabolism*; D041905:Erythroid Cells / Q000378:metabolism*; D006706:Homeostasis / Q000502:physiology*; D019012:Integrin beta1 / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D055503:Protein Multimerization / Q000502:physiology*; D017382:Reactive Oxygen Species / Q000378:metabolism*
chemical_list: D000975:Antioxidants; D019012:Integrin beta1; D017382:Reactive Oxygen Species